Safety and Efficacy of Combined Tixagevimab and Cilgavimab Administered Intramuscularly or Intravenously in Nonhospitalized Patients With COVID-19: 2 Randomized Clinical Trials

Abstract

Importance: Development of effective, scalable therapeutics for SARS-CoV-2 is a priority.

Objective: To test the efficacy of combined tixagevimab and cilgavimab monoclonal antibodies for early COVID-19 treatment.

Design, setting, and participants: Two phase 2 randomized blinded placebo-controlled clinical trials within the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-2/A5401 platform were performed at US ambulatory sites. Nonhospitalized adults 18 years or older within 10 days of positive SARS-CoV-2 test and symptom onset were eligible and were enrolled from February 1 to May 31, 2021.

Interventions: Tixagevimab-cilgavimab, 300 mg (150 mg of each component) given intravenously (IV) or 600 mg (300 mg of each component) given intramuscularly (IM) in the lateral thigh, or pooled placebo.

Main outcomes and measures: Coprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLOQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events through 28 days.

Results: A total of 229 participants were randomized for the IM study and 119 were randomized for the IV study. The primary modified intention-to-treat population included 223 participants who initiated IM tixagevimab-cilgavimab (n = 106) or placebo treatment (n = 117) (median age, 39 [IQR, 30-48] years; 113 [50.7%] were men) and 114 who initiated IV tixagevimab-cilgavimab (n = 58) or placebo treatment (n = 56) (median age, 44 [IQR, 35-54] years; 67 [58.8%] were women). Enrollment in the IV study was stopped early based on a decision to focus on IM product development. Participants were enrolled at a median of 6 (IQR, 4-7) days from COVID-19 symptom onset. Significant differences in time to symptom improvement were not observed for IM tixagevimab-cilgavimab vs placebo or IV tixagevimab-cilgavimab vs placebo. A greater proportion in the IM tixagevimab-cilgavimab arm (69 of 86 [80.2%]) than placebo (62 of 96 [64.6%]) had nasopharyngeal SARS-CoV-2 RNA below LLOQ at day 7 (adjusted risk ratio, 1.33 [95% CI, 1.12-1.57]) but not days 3 and 14; the joint test across time points favored treatment (P = .003). Differences in the proportion below LLOQ were not observed for IV tixagevimab-cilgavimab vs placebo at any of the specified time points. There were no safety signals with either administration route.

Conclusions: In these 2 phase 2 randomized clinical trials, IM or IV tixagevimab-cilgavimab was safe but did not change time to symptom improvement. Antiviral activity was more evident in the larger IM trial.

Trial registration: ClinicalTrials.gov Identifier: NCT04518410.

Figure 1.. Time to Symptom Improvement and Return to Usual Health

Participants include those treated with a tixagevimab-cilgavimab (T-C) combination administered as 600 mg intramuscularly (IM) or placebo or as 300 mg intravenously (IV) or placebo.

Figure 2.. Virologic Outcomes of Tixagevimab-Cilgavimab (T-C) Treatment

Proportion of participants with SARS-CoV-2 RNA on nasopharyngeal swabs below the limit of detection (LOD [1.4 log₁₀ copies/mL]), at or above the LOD but below the lower limit of quantitation (LLOQ [2.0 log₁₀ copies/mL]), or with quantifiable SARS-CoV-2 RNA levels (≥LLOQ) on days 0, 3, 7, 14, and 28 by site-collected nasopharyngeal swab are shown for T-C treatment groups receiving 600 mg intramuscularly (IM) and 300 mg intravenously (IV). SARS-CoV-2 log₁₀ copies/mL levels in nasopharyngeal swabs for the T-C and placebo arms are shown at each of the same days in the IM and IV groups. B and D, Middle horizontal lines represent medians; outer horizontal lines of the boxes, IQRs; and whiskers, ranges.